US3795681A - Aminothiophene-carboxylic acid esters - Google Patents
Aminothiophene-carboxylic acid esters Download PDFInfo
- Publication number
- US3795681A US3795681A US00257180A US3795681DA US3795681A US 3795681 A US3795681 A US 3795681A US 00257180 A US00257180 A US 00257180A US 3795681D A US3795681D A US 3795681DA US 3795681 A US3795681 A US 3795681A
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- carboxylic acid
- aminothiophene
- low molecular
- alkyl
- acid esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
NOVEL AMINOTHIOPHENE-CARBOXYLIC ACID ESTERS ARE DESCRIBED AS WELL AS A PROCESS FOR THEIR MANUFACTURE AND THEIR ANTIPHLOGISTIC AND ANTIPYRETIC ACTION. THE NOVEL COMPOUNDS CORRESPOND TO THE FORMULA I
2-R1,3-(R-NH-),4-(R4-COO-CH(-R3)-OOC-),5-R2-THIOPHENE
WHEREIN R REPRESENTS PHENYL WHICH MAY CARRY 1, 2 OR 3 SUBSTITUENTS SELECTED FROM HALOGEN, TRIFLUOROMETHYL, LOW MOLECULAR ALKYL AND ALKOXY, ARALKOXY BEING LOW MOLECULAR IN THE ALKYLENE MOIETY, AND CYCLOALKYL HAVING 5-6 MEMBERS, AND WHEREIN TWO VICINAL SUBSTITUENTS MAY BE MEMBERS OF A CONDENSED ALICYCLIC RING SYSTEM, AND WHEREIN R1 AND R2 EACH REPRESENTS HYDROGEN OR LOW MOLECULAR ALKYL, R3 REPRESENTS HYDROGEN OR LOW MOLECULAR ALKYL AND R4 REPRESENTS ALKYL OR ARYL IN WHICH CASE THE ARYL GROUP MAY CONTAIN 1 OR 2 HETERO ATOMS, SUCH AS NITROGEN, OXYGEN OR SULFUR.
2-R1,3-(R-NH-),4-(R4-COO-CH(-R3)-OOC-),5-R2-THIOPHENE
WHEREIN R REPRESENTS PHENYL WHICH MAY CARRY 1, 2 OR 3 SUBSTITUENTS SELECTED FROM HALOGEN, TRIFLUOROMETHYL, LOW MOLECULAR ALKYL AND ALKOXY, ARALKOXY BEING LOW MOLECULAR IN THE ALKYLENE MOIETY, AND CYCLOALKYL HAVING 5-6 MEMBERS, AND WHEREIN TWO VICINAL SUBSTITUENTS MAY BE MEMBERS OF A CONDENSED ALICYCLIC RING SYSTEM, AND WHEREIN R1 AND R2 EACH REPRESENTS HYDROGEN OR LOW MOLECULAR ALKYL, R3 REPRESENTS HYDROGEN OR LOW MOLECULAR ALKYL AND R4 REPRESENTS ALKYL OR ARYL IN WHICH CASE THE ARYL GROUP MAY CONTAIN 1 OR 2 HETERO ATOMS, SUCH AS NITROGEN, OXYGEN OR SULFUR.
Description
United States Patent US. Cl. 260-332.2 C 12 Claims ABSTRACT OF THE DISCLOSURE Novel aminothiophene-carboxylic acid esters are described as well as a process for their manufacture and their antiphlogistic and antipyretic action. The novel compounds correspond to the Formula I The present invention relates to aminothiophene-carboxylic acid esters having an antiphlogistic and antipyretic action and a process for their preparation.
Aminothiophene derivatives having antiphlogistic and antipyretic properties have been described in British Pat. No. 1,133,850.
This invention relates to aminothiophene-carboxylic acid esters of the Formula I wherein R represents phenyl which may carry 1, 2 or 3 substituents selected from halogen, trifiuoromethyl, low molecular alkyl and alkoxy, aralkoxy being low molecular in the alkylene moiety, and cycloalkyl having 5-6 members, and wherein two vicinal substituents may be members of a condensed alicyclic ring system, and wherein R and R each represents hydrogen or low molecular alkyl,
R represents hydrogen or low molecular alkyl, and
R represents alkyl or aryl in which case the aryl group may contain 1 or 2 hetero atoms, such as nitrogen, oxygen or sulfur.
Aminothiophene-carboxylic acid esters of the Formula I are preferred wherein R represents a phenyl radical which may carry 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, trifiuoromethyl, alkyl having from 1 to 4 carbon atoms, methoxy, benzyloxy, cyclopentyl, cyclohexyl, butylene-(1,4) and wherein R and R each represents hydrogen, methyl or ethyl. The radicals R and R are of minor importance with respect to the action of the substances in accordance with the invention and may therefore be varied within 3,795,681 Patented Mar. 5, 1974 wide limits. Thus, R may represent, for example, hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl and R may represent hydrogen, alkyl having from 1-1O carbon atoms, phenyl, naphthyl, pyridyl, thienyl, furyl, in which case the cyclic radicals may be substituted by low molecular alkyl, trifiuoromethyl, nitro, halogen or low molecular alkoxy.
This invention furthermore relates to a process for the preparation of an aminothiophene-carboxylic acid ester of the Formula I. which comprises reacting an aminothiophene-carboxylic acid ester of the Formula II wherein R, R and R are as defined above, or a salt of such an acid with an ester of the Formula III X-CHOOO-R,
a wherein X stands for a halogen atom, preferably a chlorine or bromine atom, or for an alkanesulfonyloxy radical, preferably a methane or ethane-sulfonyloxy radical, or an arylsulfonyloxy radical, preferably the benzene or toluene sulfonyloxy radical or the radical of the sulfur atom and R and R are as defined above.
Convenient starting materials for the process in accordance with the invention are, for example, the following aminothiophene-carboxylic acid esters corresponding to the above Formula II and the salts thereof:
These starting materials can be obtained according to process as described in British Pat. No. 1,133,850.
Suitable esters of Formula III are, for example, the following: acetoxymethyl chloride, trimethyl-acetoxymethyl chloride, propionyloxy-methyl chloride, butyryloxymethyl chloride, l-acetoxy-l-chloroethane, 1-acetoxy-1-chlorobutane, l-benzoyloxy-l-chlorethane or 1 toluyloxy-lchlorethane, nicotinoyloxymethylbromide, furoyloxymethyl chloride, thenoyloxy-methyl chloride.
The process is advantageously carried out by reacting a salt of the aminothiophene-carboxylic acid of the Formula II, preferably an alkali metal salt, in an inert solvent, such as benzene, toluene, dioxan, glycoldimethyl ether or dimethyl form-amide with an ester of the Formula III at a temperature within the range of from room temperature to the boiling temperature of the solvent used, preferably at a temperature within the range of from 40 to C., advantageously while stirring. After having separated the solvent by distillation the residue is taken up with water and an organic solvent and the reaction product is isolated from the organic solvent.
The aminothiophene-carboxylic acid esters are in some cases obtained as crystalline substances and can be purified by the habitual methods, such as recrystallization or distillation under highly reduced pressure.
The aminothiophene-carboxylic acid esters pertaining to the above-mentioned invention possess strong anti-inflammatory and antipyretic properties. Thus, for example, the examination of the 3-(2'-chloro-3'-methyl-anilino)- thiophene-carboxylic acid-acetoxymethyl ester in the Aerosil test on the rats paw (cf. Wagner-Jauregg and Jahn, Helvetica Physiologica et Pharmacologica Acta, 21 (1963), pp. 65 et seq.) upon oral administration resulted in an anti-infiammatory effect 8 to times stronger than that obtained with phenyl-butazone.
The same results were obtained in the cotton-pellet-test (Meier, Schuler and Dessaulles, Experientia, 6 (Basel 1950), pp. 469 et seq.). A strong anti-inflammatory activity could also be demonstrated using the UV-erythema test in guinea pigs (cf. Winder et al., Archives Internationales de Pharmacodynamie et de Thrapie, 116 (1958), pp. 261 et seq.).
3-(2'-chloro -3' methyl-anilino)-thiophene-carboxylic acid-acetoxy-methyl ester has considerably higher antipyretic activity in comparison to known compounds. Thus, according to the method of Bavin et al. (cf. Journal of Pharmacy and Pharmacology 4 (1932), pp. 872 et seq.) 2.5 milligrams/kg. of the above-mentioned compound given orally to rats showed the same antipyretic activity as 16 milligrams/kg. of phenylbutazone. The compound pertaining to the invention acted as an analgesic (cf. phenylquinone-Writhing test, by the method described by Hendershot and Forsaith, Journal of Pharmacology and Experimental Therapeutics, 125 (1959), pp. 237 et seq.). The activity in this test is 10 times stronger than that obtained with phenylbutazone or aminophenazone.
The acute toxicity of the compounds in accordance with the invention is low and it lies in the same range or is even less than the toxicity of the known compounds mentioned.
The aminothiophene-carboxylic acid esters of the invention can, therefore, be used as antiphlogistics, antipyretics and analgesics.
They are tasteless and can be further worked, optionally in admixture with other active substances, in the form of the usual galenic preparations with the habitually used excipients, solvents or constituents. For oral and rectal administration, tablets, capsules and drages or suppositories are preferably used. Injection in physiologically tolerable solvents and the local administration in the form of solutions, ointments or powders are also possible.
The following examples illustrate the invention.
EXAMPLES (1) 3-(2'-chloro 3 methylanilino)-thiophene-4-carboxylic acid acetoxy-methyl ester.--26.8 g. of 3-(2'- chloro-3-methylanilino)-thiophene 4 carboxylic acid were heated at 60 C. in 250 ml. of dimethyl formamide in the presence of 14 g. of potassium carbonate. g. of chloromethyl acetate were added to the mixture and stirred at 60 C. for 1 hour. The reaction mixture was vaporized and the residue was taken up in trichloromethane and water. After washing with water, drying with sodium sulfate and vaporization the acetoxymethyl ester was obtained from the organic phase which was purified by recrystallization from diisopropyl ether.
Yield: 21.2 g.
Melting point: 80" C.
Boiling point: 205-208 C. under a pressure of 0.1 mm. mercury.
In an analogous manner, the following compounds were obtained.
(2) 3-(2-chloro-3'-methylanilino)-thiophene 4 carboxylic acid-trimethyl-acetoxymethyl ester; boiling point: 205207 C. under a pressure of 0.1 mm. mercury.
(3) 3-(2-chloro-3'-methylanilino)-thiophene 4 carboxylic acid-butyryloxy methylester; melting point: 65 C.
4) 3-(3,5'-bis-trifiuoromethyl) anilino thiophene-4- carboxylic acid-acetoxymethylester; melting point: 93 C.
(5) 3-(2',6'-dichloroanilino)-thiophene 4 carboxylic acid-acetoxy-methyl ester; melting point: 59 C.
(6) 3-(2'-chloro-5-trifluoromethylanilino)-thiophene- 4-carboxylic acid-acetoxymethyl ester; melting point 101 C.
(7) 3-(2'-chloro-3'-methylanilino)-thiophene 4 carboxylic acid-a-(p-chlorobenzoyloxy)ethyl ester; melting point: 107 C.
We claim:
1. A11 aminothiophene-carboxylic acid ester of the formula 0 r R-NH iL-O-(fH-O-iJ-R. R3 R1 R: s
wherein R represents phenyl substituted by from 1 to 3 substituents selected from the group consisting of halogen, trifluoromethyl, lower alkyl, lower alkoxy, benzyloxy and cycloalkyl of 5 to 6 carbon atoms and 1,4-butylene substituted on vicinal carbon atoms, R and R represent hydrogen or lower alkyl, R represents hydrogen or alkyl of 1 to 6 carbon atoms, and R represents hydrogen, alkyl of 1 to 10 carbon atoms, phenyl, naphthyl, pyridyl, thienyl, furyl or phenyl substituted by lower alkyl, trifiuoromethyl, nitro, halogen or lower alkoxy.
2. An aminothiophene-carboxylic acid ester as defined in claim 1 wherein R represents phenyl substituted by from 1 to 3 substituents selected from the group consisting of chlorine, trifiuoromethyl and methyl.
3. An aminothiophene-carboxylic acid ester as defined in claim 1 wherein R and R are hydrogen,-methyl, ethyl, propyl or butyl.
4. An aminothiophenc-carboxylic acid ester as defined in claim 1 wherein R is hydrogen, methyl, ethyl or P py 5. An aminothiophene-carboxylic acid ester as defined in claim 1 wherein R is hydrogen, methyl, ethyl, propyl, isobutyl, phenyl, tolyl, chlorophenyl, pyridyl, thienyl or furyl.
6. The compound defined in claim 1 wherein R is 2- chloro-3'-methylphenyl, R R and R are hydrogen, and R is methyl.
7. The compound defined in claim 1 wherein R is 2'- chloro-3'-methylphenyl, R R and R are hydrogen, and R4 is -C(CH3)3.
8. The compound defined in claim 1 wherein R is 2'- chloro-3'-methylphenyl, R R and R are hydrogen, and R4 iS C3'H9.
9. The compound defined in claim 1 wherein R is 3,5'- bis-trifiuoromethylphenyl, R R and R are hydrogen and R is methyl.
10. The compound defined in claim 1 wherein R is 2',6'-dichlorophenyl, R R and R are hydrogen, and R is methyl.
11. The compound defined in claim 1 wherein R is 2- chloro-S'-trifluoromethylphenyl, R R and R are hydrogen, and R is methyl.
12. The compound defined in claim 1 wherein R is 2'- chloro-3'-methylphenyl, R and R are hydrogen, R is methyl and R is p-chlorophenyl.
References Cited UNITED STATES PATENTS 5/1969 Ruschig et al. 260-2934
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19712126597 DE2126597A1 (en) | 1971-05-28 | 1971-05-28 | Aminothiophenecarboxylic acid esters and process for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3795681A true US3795681A (en) | 1974-03-05 |
Family
ID=5809209
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00257180A Expired - Lifetime US3795681A (en) | 1971-05-28 | 1972-05-26 | Aminothiophene-carboxylic acid esters |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US3795681A (en) |
| AR (1) | AR197680A1 (en) |
| AT (1) | AT321904B (en) |
| AU (1) | AU4278672A (en) |
| BE (1) | BE784121A (en) |
| CA (1) | CA983038A (en) |
| DD (2) | DD101406A5 (en) |
| DE (1) | DE2126597A1 (en) |
| ES (1) | ES403080A1 (en) |
| FR (1) | FR2139960B1 (en) |
| GB (1) | GB1386664A (en) |
| HU (1) | HU165931B (en) |
| IL (1) | IL39546A0 (en) |
| NL (1) | NL7206924A (en) |
| ZA (1) | ZA723614B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4032647A (en) * | 1975-06-16 | 1977-06-28 | Richardson-Merrell Inc. | Substituted thenoylacetic acid and esters |
| US4299968A (en) * | 1973-12-03 | 1981-11-10 | Hoffmann-La Roche Inc. | Novel thiophene compounds |
| US4317915A (en) * | 1976-08-23 | 1982-03-02 | Hoffmann-La Roche Inc. | Novel thiophene derivatives |
| US4360681A (en) * | 1973-12-03 | 1982-11-23 | Hoffmann-La Roche Inc. | Novel thiophene compounds |
| US4428963A (en) | 1976-08-23 | 1984-01-31 | Hoffmann-La Roche Inc. | Novel thiophene derivatives |
| US5352692A (en) * | 1991-04-04 | 1994-10-04 | Laevosan Gesellschaft M. B. H. | Thiophene-2-carboxylic acid derivatives |
-
1971
- 1971-05-28 DE DE19712126597 patent/DE2126597A1/en active Pending
-
1972
- 1972-05-19 CA CA143,066A patent/CA983038A/en not_active Expired
- 1972-05-23 NL NL7206924A patent/NL7206924A/xx unknown
- 1972-05-23 ES ES403080A patent/ES403080A1/en not_active Expired
- 1972-05-25 GB GB2464072A patent/GB1386664A/en not_active Expired
- 1972-05-26 IL IL39546A patent/IL39546A0/en unknown
- 1972-05-26 AT AT459972A patent/AT321904B/en not_active IP Right Cessation
- 1972-05-26 DD DD163228A patent/DD101406A5/xx unknown
- 1972-05-26 AU AU42786/72A patent/AU4278672A/en not_active Expired
- 1972-05-26 US US00257180A patent/US3795681A/en not_active Expired - Lifetime
- 1972-05-26 FR FR7218875A patent/FR2139960B1/fr not_active Expired
- 1972-05-26 AR AR242190A patent/AR197680A1/en active
- 1972-05-26 ZA ZA723614A patent/ZA723614B/en unknown
- 1972-05-26 DD DD172612*A patent/DD105991A5/xx unknown
- 1972-05-27 HU HUHO1488A patent/HU165931B/hu unknown
- 1972-05-29 BE BE784121A patent/BE784121A/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4299968A (en) * | 1973-12-03 | 1981-11-10 | Hoffmann-La Roche Inc. | Novel thiophene compounds |
| US4360681A (en) * | 1973-12-03 | 1982-11-23 | Hoffmann-La Roche Inc. | Novel thiophene compounds |
| US4032647A (en) * | 1975-06-16 | 1977-06-28 | Richardson-Merrell Inc. | Substituted thenoylacetic acid and esters |
| US4317915A (en) * | 1976-08-23 | 1982-03-02 | Hoffmann-La Roche Inc. | Novel thiophene derivatives |
| US4428963A (en) | 1976-08-23 | 1984-01-31 | Hoffmann-La Roche Inc. | Novel thiophene derivatives |
| US5352692A (en) * | 1991-04-04 | 1994-10-04 | Laevosan Gesellschaft M. B. H. | Thiophene-2-carboxylic acid derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| DD105991A5 (en) | 1974-05-20 |
| FR2139960B1 (en) | 1975-04-25 |
| AU4278672A (en) | 1973-11-29 |
| GB1386664A (en) | 1975-03-12 |
| HU165931B (en) | 1974-12-28 |
| CA983038A (en) | 1976-02-03 |
| AT321904B (en) | 1975-04-25 |
| ES403080A1 (en) | 1975-04-16 |
| DD101406A5 (en) | 1973-11-05 |
| AR197680A1 (en) | 1974-04-30 |
| NL7206924A (en) | 1972-11-30 |
| ZA723614B (en) | 1973-03-28 |
| IL39546A0 (en) | 1972-07-26 |
| BE784121A (en) | 1972-11-29 |
| DE2126597A1 (en) | 1972-12-14 |
| FR2139960A1 (en) | 1973-01-12 |
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